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This phase III trial is studying observation to see how well a risk based treatment strategy works in patients with soft tissue sarcoma. In the study, patients are assigned to receive surgery +/- radiotherapy +/- chemotherapy depending on their risk of recurrence. Sometimes, after surgery, the tumor may not need additional treatment until it progresses. In this case, observation may be sufficient. Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as ifosfamide and doxorubicin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving chemotherapy and radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving these treatments after surgery may kill any tumor cells that remain after surgery.

V. Correlate patient outcomes with findings of biologic studies performed on tissue specimens collected on protocol COG-D9902 from these patients.

VI. Determine whether the diagnosis and histologic grade of NRSTS assigned by the enrolling institution correlates with the diagnosis and histologic grade established by central expert pathology reviewers.

REGIMEN C (adjuvant chemoradiotherapy): Patients receive ifosfamide IV over 3 hours on days 1-3 in weeks 1, 4, 7, 10, 13, and 16 and doxorubicin hydrochloride IV over 24 hours on days 1 and 2 in weeks 1, 4, 13, 16, and 19. Beginning in week 4, patients also undergo a total of 31 fractions of radiotherapy.

*NOTE: *Patients who receive brachytherapy will initiate radiotherapy in Week 1. If brachytherapy is administered, chemotherapy should begin within 2 weeks of completion of brachytherapy and the Weeks 1 and 19 doxorubicin should be given instead at Weeks 7 and 10.

REGIMEN D (neoadjuvant chemoradiotherapy, surgery, and adjuvant chemotherapy with or without radiotherapy): Neoadjuvant chemoradiotherapy and surgery: Patients receive ifosfamide IV over 3 hours on days 1-3 in weeks 1, 4, 7, and 10 and doxorubicin hydrochloride IV over 24 hours on days 1 and 2 in weeks 1 and 4. Beginning in week 4, patients also undergo a total of 31 fractions of radiotherapy**. Patients undergo surgical resection in week 13.

NOTE: **Patients with primary hepatic tumors do not receive radiotherapy in week 4.

Adjuvant chemotherapy with or without radiotherapy: Patients receive ifosfamide IV over 3 hours on days 1-3 in weeks 16 and 19 and doxorubicin hydrochloride IV over 24 hours on days 1 and 2 in weeks 16, 19***, and 22. Beginning in week 16, patients achieving gross total resection with positive microscopic margins undergo a total of 6 fractions of adjuvant radiotherapy. Patients achieving less than total gross resection undergo a total of 11 fractions of adjuvant radiotherapy. Patients achieving total gross resection with negative microscopic margins do not receive adjuvant radiotherapy.

GROUP 3 (high risk [metastatic, resected, incompletely resected, or unresected disease]): Patients with low-grade, all-sites resected tumor with either negative or positive microscopic margins are assigned to receive treatment as in group 1 regimen A. Patients with high-grade, grossly resected primary tumor, and metastatic disease are assigned to receive treatment as in group 2 regimen C. Patients with unresected, high-grade metastatic tumor are assigned to receive treatment as in group 2 regimen D.

In all groups, treatment continues in the absence of disease progression. After completing study treatment, patients are followed periodically for at least 5 years.

Probability of no relapse, secondary malignancy or death after 5 years since enrollment

Overall Survival Probability Disease Extent [ Time Frame: 5 years ]

Probability of survival after 5 years since enrollment.

Overall Survival Probability Extent of Resection of the Primary Tumor [ Time Frame: 5 years ]

Probability of survival after 5 years since enrollment.

Incidence of Distant Metastasis [ Time Frame: Up to 10 years ]

Percent of patients who had distant metastasis.

Genetic and Gene Expression Profiles [ Time Frame: At diagnosis ]

The tumors from patients registered on D9902 will be analyzed for genetic and gene expression profiles. The study will prospectively evaluate each tumor and confirm newly defined sarcoma diagnostic criteria based on cancer signatures in NRSTS.

Degree of Agreement in Histologic Grade Determined by the Enrolling Institution Versus by Central Pathology Reviewers [ Time Frame: At Diagnosis ]

Histologic grades were determined by the central pathology reviewers and institutional pathologists based on published standards. A higher grade is associated with a more severe disease.

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Tumor of either high- or- low-grade that cannot be grossly excised without unacceptable morbidity

High-grade tumor with metastases

Patients with metastatic low-grade tumor whose disease is amenable to gross resection at all sites must undergo gross resection of all sites prior to study entry

Patients with a tumor recurrence after a gross total resection are not eligible

Tumors arising in bone are not eligible

Patients with epithelioid sarcoma, clear cell sarcoma, or clinical or radiologic evidence of regional lymph node enlargement must undergo sentinel lymph node biopsies or lymph node sampling to confirm the status of regional lymph nodes* NOTE: *Except in cases where the study radiologist reviews the imaging and indicates that a biopsy is not needed to confirm that the patient has lymph node involvement.

If lymph node biopsies are positive for tumor (or the lymph nodes are classified as positive by the study radiologist), formal lymph node dissection must be done at the time of definitive surgery(prior to study entry for patients assigned to study regimen C)

Patients with metastatic disease must undergo a biopsy to confirm the presence of metastatic tumor if all metastases are < 1 cm in maximal diameter (except in cases where the study radiologist reviews the imaging and indicated that a biopsy is not needed to confirm that the patient has metastatic disease)

Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min (≥ 40 mL/min for infants < 1 year of age)* or serum creatinine based on age and/or gender as follows:

0.4 mg/dL (1 month to < 6 months of age)

0.5 mg/dL (6 months to < 1 year of age)

0.6 mg/dL (1 year to < 2 years of age)

0.8 mg/dL (2 years to < 6 years of age)

1.0 mg/dL (6 years to < 10 years of age)

1.2 mg/dL (10 years to < 13 years of age)

1.5 mg/dL (male) or 1.4 mg/dL (female) (13 years to < 16 years of age)

1.7 mg/dL (male) or 1.4 mg/dL (female) (≥ 16 years of age)

Patients with urinary tract obstruction by tumor must meet the renal function criteria listed above AND must have unimpeded urinary flow established via decompression of the obstructed portion of the urinary tract